Sustained-release formulations of topiramate

ABSTRACT

Pharmaceutical compositions of topiramate for once-a-day oral administration are provided. The formulations comprise a sustained-release component and an optional immediate-release component, the compositions of which can be selectively adjusted, respectively, to release the active ingredient along a pre-determined release profile. Method of treating or preventing pathological disorders in mammalian subjects comprising the administration of the novel formulations disclosed herein is also provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims benefit of U.S. Provisional ApplicationNo. 60/859,502, filed Nov. 17, 2006, the entire contents of which areincorporated herein by reference.

BACKGROUND OF THE INVENTION

Topiramate is a sulfamate substituted monosaccharide which under thetrade name TOPAMAX® (Ortho-McNeil Pharmaceutical, Inc., Raritan, N.J.,U.S.A.) has been approved for use as an antiepileptic agent, as anadjuvant therapy for patients with partial onset seizures or primarygeneralized tonic-clonic seizures, and for the prevention of migraine.See generally, Physician's Desk Reference, 60th ed., 2538-2447 (2006);see also, U.S. Pat. No. 4,513,006.

For the treatment of epilepsy, the recommended dose of TOPAMAX® is 400mg/day in one or multiple doses (Physician's Desk Reference, 60th ed.,2538-2447 (2006)). For adults with epilepsy, treatment is initiated witha dose of 25-50 mg/day, with the dose being titrated in increments of25-50 mg at weekly intervals to the recommended or effective dose.

TOPAMAX® is an immediate release formulation. Adverse effects associatedwith the administration of TOPAMAX® include, but are not limited to,somnolence, dizziness, ataxia, speech disorders and related speechproblems, psychomotor slowing, abnormal vision, difficulty with memory,paresthesia, diplopia, renal calculi (kidney stones), hepatic failure,pancreatitis, renal tubular acidosis, acute myopia and secondary angleclosure glaucoma (Physician's Desk Reference, 60th ed., 2538-2447(2006)).

Hence, though topiramate has a relatively long half-life of 21 hours invivo, it has not been prescribed (or formulated) as a single,daily-dose, in part due to severe side-effects that often result withpeak plasma levels of the drug when taken in high doses. Instead,TOPAMAX® is typically taken in multiple, “divided” doses, usuallytwice-daily (“BID”). However, administration of the medicament in thismanner is cumbersome and patients can forget to take their medication ina timely manner. What is more, each administration of a dose isassociated with a peak in plasma concentrations of the drug, and thefluctuations associated with the peaks and valleys of blood plasmalevels of the drug are undesirable. Therefore, there is a need for aformulation of topiramate, which reduces or eliminates the side effectsassociated with peaking and fluctuating plasma levels of the drug andpreferably may be administered in a once-daily regimen.

New, highly soluble and bioavailable forms of topiramate are also neededin order to increase the safety and effectiveness of the drug.

The instant invention addresses these and other needs by providing amodified formulation of topiramate characterized by a sustained,non-pulsatile release of an active ingredient. This inventionadditionally provides an effective, once-daily dosage form of topiramateor salts thereof, which not only enables an effective single daily doseregimen to improve patient compliance but may also reduce some of theside effects of topiramate compared to the current or higher daily dosesof immediate release topiramate formulations.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a sustained releaseformulation of topiramate for the treatment or prevention of apathological condition in a mammalian subject, characterized by asustained rate of topiramate release along a pre-determined releaseprofile.

It is yet another object of the present invention to provide topiramateformulation wherein topiramate is released at a rate which results in areduction in the frequency or severity of at least one side effectassociated with the topiramate treatment.

It is a further object of the present invention to provide a sustainedrelease formulation of topiramate that can be administered orally once aday.

It is an object of the present invention to provide a sustained releaseformulation of topiramate for oral administration to a mammalian subjectcomprising topiramate as an active ingredient, wherein the activeingredient is released from the formulation at a sustained rate along apre-determined release profile, and wherein the sustained releaseformulation comprises an extended release (XR) component and an optionalimmediate release (IR) component.

In one embodiment of the invention, the extended release component iscontained in at least one population of beads coated with a releasecontrolling coating. The above-mentioned coating is specific for everybead population and determines its rate of release. Thus, every givenbead population included into the formulation is characterized by itsown specific rate of release.

In another embodiment of the invention, the sustained release topiramateformulation comprises an immediate release component in addition to anextended release component.

In a preferred embodiment of the invention, the immediate releasecomponent is an enhanced immediate release (EIR) composition.

The formulation of the present invention may be incorporated in any oraldosage form such as represented by, but not limited to, a tablet, apill, a capsule, a troche, a sachet, and sprinkles.

It is yet another object of the present invention to provide a method ofpreparation of a sustained release formulation of topiramate, comprisingan extended release component, and an optional immediate releasecomponent, wherein topiramate is released from the formulation at thesustained rate along the pre-determined release profile, the methodcomprising the steps of:

1. determining the desired release profile;

2. determining specific amounts of the extended release component andthe immediate release component necessary to produce the pre-determinedrelease profile; and

3. incorporating the specified amounts of the components into theformulation.

In one embodiment, the method of preparation additionally includes aprocess for providing an XR component contained in at least onepopulation of beads, wherein every population of beads is characterizedby its own rate of release. This process comprises the steps of

1. forming at least one population of topiramate-containing beads;

2. coating each population of beads with its own coating solution;

3. curing the coating for a period of time to produce a releasecontrolling coating specific for each bead population, and

4. incorporating the beads into the formulation.

The method may optionally include a process for preparation of an IRcomponent, which optionally is an enhanced immediate release (EIR)composition. The enhanced immediate release composition includes atleast one agent selected from a group comprising complexing agents andenhancing agents. Without any limitations, the enhancing agents usefulin the present invention may be selected from solubilizing agents,dissolution enhancing agents, absorption enhancing agents, penetrationenhancing agents, surface active agents, stabilizing agents, enzymeinhibitors, p-glycoprotein inhibitors, multidrug resistance proteininhibitors or combinations thereof.

It is yet another object of the present invention to provide a method oftreatment or prevention of a pathological condition in a mammaliansubject by orally administering to the subject a therapeuticallyeffective amount of a sustained release topiramate formulation of theinstant invention. The pathological conditions that may be treated bythe method of the present invention include neurological condition,psychiatric condition, diabetes and related disorders, cardiovascularcondition, obesity, and any other condition or disorder that may betreated or prevented by topiramate administration.

Definitions:

For the purposes of this invention, the term “topiramate” includestopiramate or any pharmaceutically acceptable salts thereof.

An “immediate release formulation” refers to a formulation that releasesgreater than or equal to about 80% of the pharmaceutical agent in lessthan or equal to about 1 hour.

For the purposes of this application, an enhancing agent (“enhancer”) isdefined as any non-pharmaceutically active ingredient that improves thetherapeutic potential of a formulation.

The term “enhanced immediate release composition” as used hereindescribes an immediate release composition improved in terms of atherapeutic potential or treatment modality.

“Sustained release” is defined herein as release of a pharmaceuticalagent in a continuous manner over a prolonged period of time.

By “prolonged period of time” it is meant a continuous period of time ofgreater than about 1 hour, preferably, greater than about 4 hours, morepreferably, greater than about 8 hours, more preferably greater thanabout 12 hours, more preferably still, greater than about 16 hours up tomore than about 24 hours.

As used herein, unless otherwise noted, “rate of release” or “releaserate” of a drug refers to the quantity of drug released from a dosageform per unit time, e.g., milligrams of drug released per hour (mg/hr)or a percentage of a total drug dose released per hour. Drug releaserates for dosage forms are typically measured as an in vitro rate ofdrug release, i.e., a quantity of drug released from the dosage form perunit time measured under appropriate conditions and in a suitable fluid.The time at which a specified percentage of the drug within a dosageform has been released from the dosage form is referred to as the“T.sub.x” value, where “x” is the percent of drug that has beenreleased.

The release rates referred to herein are determined by placing a dosageform to be tested in a medium in an appropriate dissolution bath.Aliquots of the medium, collected at pre-set intervals, are theninjected into a chromatographic system fitted with an appropriatedetector to quantify the amounts of drug released during the testingintervals.

“C” denotes the concentration of drug in blood plasma, or serum, of asubject, and is generally expressed as mass per unit volume, for examplenanograms per milliliter. For convenience, this concentration may bereferred to herein as “drug plasma concentration”, “plasma drugconcentration” or “plasma concentration” which is intended to beinclusive of a drug concentration measured in any appropriate body fluidor tissue. The plasma drug concentration at any time following drugadministration is referenced as Ctime, as in C9hr or C4hr, etc.

The maximum plasma drug concentration during the dosing period isreferenced as Cmax, while Cmin refers to the minimum blood plasma drugconcentration at the end of a dosing interval; and Cave refers to anaverage concentration during the dosing interval.

The “degree of fluctuation” is defined as a quotient (Cmax−Cmin)/Cave.

Persons of skill in the art will appreciate that blood plasma drugconcentrations obtained in individual subjects will vary due tointerpatient variability in the many parameters affecting drugabsorption, distribution, metabolism and excretion. For this reason,unless otherwise indicated, when a drug plasma concentration is listed,the value listed is the calculated mean value based on values obtainedfrom a groups of subjects tested.

The term “bioavailability” refers to an extent to which—and sometimesrate at which—the active moiety (drug or metabolite) enters systemiccirculation, thereby gaining access to the site of action.

“AUC” is the area under the plasma concentration-time curve and isconsidered to be the most reliable measure of bioavailability. It isdirectly proportional to the total amount of unchanged drug that reachesthe systemic circulation.

Side effect is defined herein as a secondary and usually adverse effectof a drug.

The term “beads”, as used herein, includes, without any limitations onthe nature and size thereof, any particles, spheres, beads, granules,pellets, particulates or any structural units that may be incorporatedinto an oral dosage form.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the time of release of 80% of the drug vs. % wt. gain ofrelease controlling coating for cured SURELEASE® (ethylcellulosedispersion) coated extended release beads.

FIG. 2 shows the time of release of 80% of the drug vs. % wt. gain ofrelease controlling coating for cured SURELEASE®/OPADRY® Clear (HPMCwith PEG) coated extended release beads.

FIG. 3 shows mean (n=16) pharmacokinetic profiles for bead populationsXR1, XR2 and XR3.

FIG. 4 shows mean (n=16) pharmacokinetic profiles for the immediaterelease formulations.

FIG. 5 shows the dissolution profiles of TOPAMAX®, topiramate IR beads,and topiramate enhanced immediate release beads.

FIG. 6 shows mean PK Profiles for Sustained Release Formulations A, B,and C.

DETAILED DESCRIPTION OF THE INVENTION

Topiramate is a sulfamate-substituted monosaccharide having the chemicalname 2,3:4,5-Di-O-isopropylidene-beta-D-fructopyranose sulfamate. Themolecular formula of topiramate is C12H21NO8S, and its chemicalstructure is represented by formula below:

Topiramate is a white crystalline powder that is soluble in alkalinesolutions containing sodium hydroxide or sodium phosphate, soluble inacetone, dimethylsulfoxide and ethanol. However, the solubility oftopiramate in water at room temperature is only about 9.8 mg/ml.Topiramate is not extensively metabolized and is excreted largelythrough the urine (Physician's Desk Reference, 60th ed., 2538-2447(2006)).

Topiramate pharmacokinetics are linear, producing a dose proportionalincrease in blood plasma concentration levels with increased dosing, andis not significantly affected by food. Patients taking topiramate overprolonged period of time did not develop resistance to the drug.Following oral administration of an immediate release dosage form,topiramate is rapidly absorbed with plasma drug concentrations peakingin approximately 2 hours. The mean elimination half-life is reported tobe about 21 hours.

Currently, topiramate is administered in multiple daily doses in partdue to the severe side effects exhibited by the immediate releaseproduct, especially when taken in a high single dose.

A sustained release topiramate formulation that will be suitable foronce-a-day administration and will result in the diminished level orseverity of side effects is needed.

The present invention provides sustained release formulation oftopiramate wherein the total daily dose of topiramate is provided in aneffective once-daily dose while minimizing fluctuations in the bloodplasma drug concentration.

The current invention also provides for formulations of topiramatewherein the maximum plasma concentration of topiramate is attenuated ascompared to the same amount of topiramate administered as an immediaterelease formulation BID; therefore some of the side effects oftopiramate, such as CNS side effects including but not limited todizziness, paresthesia, nervousness, psychomotor slowing, confusion, anddifficulty with concentration/attention, observed when taking theimmediate release product, may be reduced or eliminated.

Formulations of the instant invention are characterized by a maximumsteady state plasma concentration (Cmax) of topiramate which is higherthan the minimal therapeutically effective concentration, and is in therange of 50% to 125% of the maximum plasma concentration produced by thesame amount of topiramate administered as an immediate releaseformulation BID. In one embodiment, the novel formulations provide for arelative Cmax in the range of 80% to 125%, as compared to the sameamount of topiramate administered as an immediate release formulationBID. In the other embodiment, the invention provides for the Cmax whichis lower than the maximum plasma concentration produced by the sameamount of topiramate administered as an immediate release formulationBID. The Cmin of the topiramate formulation of the present invention isabout equal or higher than a Cmin of an equivalent amount of immediaterelease topiramate formulation given BID.

Compared to the immediate release topiramate formulation, the sustainedrelease topiramate formulations attenuate the Cmax of topiramate whileextending the coverage of plasma concentration above the minimum plasmaconcentration required therapeutic efficacy. The formulation of thecurrent invention provides for a relative steady state AUC in the rangeof 80% to 125%, while minimizing the degree of fluctuation, which ispreferably in the range of 25% to 90%, as compared to an equivalentamount of immediate release topiramate formulation given in two divideddoses (Table 5 and 6).

The present invention additionally provides a sustained releasetopiramate formulation for the treatment or prevention of a pathologicalcondition in a mammalian subject wherein topiramate is released from theformulation at a sustained rate along a pre-determined release profile.Such release is achieved by incorporation into the formulation of anextended release component (XR) and an optional immediate releasecomponent (IR).

The relative amount of each component in the topiramate formulation ofthe present invention is determined according to the purpose ofadministration and a pre-determined release profile, and the totalamount of topiramate in the formulation varies from 0.5 mg to about 3000mg. In other words, topiramate or its salt is present in the compositionin an amount of from about 0.5% to about 85% by weight, and preferablyof from about 2% to about 70% by weight. The term “about” has beenrecited here and throughout the specification to account for variations,which can arise from inaccuracies in measurement inherent and understoodby those of ordinary skill in the chemical and pharmaceutical arts.

The XR component of the formulation of the present invention releasestopiramate in a continuous manner and is adjusted in such a way that 80%of the active ingredient is released in vitro in the predeterminedperiod of time. By way of example, and by no means limiting the scope ofthe invention, the period of time may be not more than 24 hours, notmore than 16 hours, not more than 12 hours, not more than 8 hours, ornot more than 4 hours, depending on desired attributes of the finalproduct.

In one embodiment, the extended release (XR) component is contained inat least one population of beads coated with a coating that modifies andcontrols the release of topiramate from the beads (release controllingcoating). The release controlling coating is specific for everypopulation of beads and determines the rate of release of topiramatefrom the given bead population.

The beads useful in the formulation of the present invention comprise aninert carrier, topiramate, a binder, an afore-mentioned releasecontrolling coating and optionally, an overcoat that provides additionalprotection from moisture, static charge reduction, taste masking andcoloring attributes to the particulates.

The inert carriers useful in the present invention may be selected from,but are not limited to, a group consisting of cellulose spheres, silicondioxide, starch and sugar spheres. The inert carrier is present in anamount of from about 15% to about 99% by weight, and preferably in anamount of from about 40% to about 97% by weight.

Topiramate is introduced to the inert carrier by techniques known to oneskilled in the art, such as drug layering, powder coating,extrusion/spheronization, roller compaction or granulation. Preferably,the introduction method is drug layering by spraying a suspension oftopiramate and a binder onto the inert carrier.

The binder may be present in the bead formulation in an amount of fromabout 0.1% to about 15% by weight, and preferably of from about 0.2% toabout 10% by weight. Binders include, but are not limited to starches,microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethylcellulose, hydroxypropylmethyl cellulose, or polyvinylpyrrolidone.

The release controlling coating specific for every bead populationcomprises a coating material, and, optionally, a pore former and otherexcipients. The coating material is preferably selected from a groupcomprising cellulosic polymers, such as ethylcellulose, methylcellulose,hydroxypropyl cellulose, hydroxypropylmethyl cellulose, celluloseacetate, and cellulose acetate phthalate; polyvinyl alcohol; acrylicpolymers such as polyacrylates, polymethacrylates and copolymersthereof, and other water-based or solvent-based coating materials. Therelease-controlling coating is population-specific in the sense that therate of release of topiramate from every bead population is controlledby at least one parameter of the release controlling coating, such asthe nature of the coating, coating level, type and concentration of apore former, process parameters and combinations thereof. Thus, changinga parameter, such as a pore former concentration, or the conditions ofthe curing, as will be discussed in more details below, (see Example 5)allows to change the release of topiramate from any given beadpopulation and to selectively adjust the formulation to thepre-determined release profile. The release profile, in its turn, may bechosen or modified in such a way as to achieve the best treatmentmodality depending on the specific needs of the patient population andthe nature of the condition.

For example, with all things being equal, there exists a mathematicalrelationship between the release controlling coating level among thecured beads and the 80% in vitro release time. Pre-determined targetprofiles can therefore be achieved by the interpolation or extrapolationof the relationship curve. For example, when the release controllingcoating comprises only ethylcellulose (SURELEASE®) as a coatingmaterial, a logarithmic relationship exists between the % weight gainwith the coating and the 80% release time in an in-vitro dissolutiontest (FIG. 1):Log(T _(80% release))=a(% coating)+b.

When ethylcellulose/HPMC (SURELEASE®/OPADRY®) mixture is used, forexample, 85:15 mixture or 80:20 mixture, a linear relationship existsbetween the % weight gain with the coating and the 80% release time inan in-vitro dissolution test (FIG. 2):T _(80% release) =a(% coating)+b.

Pore formers suitable for use in the release controlling coating hereincan be organic or inorganic agents, and include materials that can bedissolved, extracted or leached from the coating in the environment ofuse. Examples of pore formers include but are not limited to organiccompounds such as mono-, oligo-, and polysaccharides including sucrose,glucose, fructose, mannitol, mannose, galactose, sorbitol, pullulan,dextran; polymers soluble in the environment of use such aswater-soluble hydrophilic polymers, hydroxyalkylcelluloses,carboxyalkylcelluloses, hydroxypropylmethylcellulose, cellulose ethers,acrylic resins, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone,polyethylene oxide, Carbowaxes, Carbopol, and the like, diols, polyols,polyhydric alcohols, polyalkylene glycols, polyethylene glycols,polypropylene glycols, or block polymers thereof, polyglycols,poly(α-ω)alkylenediols; inorganic compounds such as alkali metal salts,lithium carbonate, sodium chloride, sodium bromide, potassium chloride,potassium sulfate, potassium phosphate, sodium acetate, sodium citrate,suitable calcium salts, and the like.

The release controlling coating in the current invention can furthercomprise other additives known in the art such as plasticizers,anti-adherents, glidants, and antifoams.

In some embodiments, it may be further desirable to optionally coat theXR beads with an “overcoat,” to provide, e.g., moisture protection,static charge reduction, taste-masking, flavoring, coloring, and/orpolish or other cosmetic appeal to the beads. Suitable coating materialsfor such an overcoat are known in the art, and include, but are notlimited to, cellulosic polymers such as hydroxypropylmethylcellulose,hydroxypropylcellulose and microcrystalline cellulose, or combinationsthereof (for example various OPADRY® coating materials).

Topiramate-containing beads of the present invention may additionallycontain enhancers that may be exemplified by, but not limited to,solubility enhancers, dissolution enhancers, absorption enhancers,permeability enhancers, stabilizers, complexing agents, enzymeinhibitors, p-glycoprotein inhibitors, and multidrug resistance proteininhibitors. Alternatively, the formulation can also contain enhancersthat are separated from the topiramate beads, for example in a separatepopulation of beads or as a powder. In yet another embodiment, theenhancer(s) may be contained in a separate layer on atopiramate-containing bead either under or above the release controllingcoating.

The beads may further comprise other pharmaceutically active agentssuitable for use in combination with topiramate for treatment orprevention of a pathological condition. The additional pharmaceuticallyactive agents, without limitation, may be represented by analgesic andanti-inflammatory compounds such as COX-2 inhibitors, nonsteroidalanti-inflammatory drugs (NSAIDs), narcotic drugs such as opiates andmorphinomimetics, synthetic drugs with narcotic properties such astramadol; anticonvulsants such as valproic acid or its derivatives,carbamazepine, oxcarbazepine, gabapentin, and lamotrigine; anorectics oranti-obesity agents such as sibutramine or other, orlistat or otherpancreatic lipase inhibitors, diethylpropion, fluoxetine, bupropion,amphetamine, methamphetamine, sertraline, zonisamide, and metformin, aswell as medications associated with weight-gain, such as sulfonylureaderivatives, insulin, and thiazolidinediones whose weight-gain effect istempered by topiramate; anti-hypertensive agents such as diuretics,anti-adrenergics, calcium channel blockers, ACE inhibitors, angiotensinII receptor antagonists, aldosterone antagonists, vasodilators,centrally acting adrenergic drugs, and adrenergic neuron blockers; moodstabilizers such as various forms/salts of lithium, Omega-3 fatty acidsand others known in the art, drugs for treatment or prevention ofmigraines, such as ergot derivatives or triptans, or any otherpharmaceutical or nutraceutical ingredient that can be safely andbeneficially combined with topiramate.

A relative amount of every bead population in the complete formulationis determined on the basis of the pharmacokinetic data of the separatebead populations and the pre-determined release profile and will bediscussed in more detail in Example 6.

In another embodiment, the formulation of the present inventioncomprises an extended release component as described above, and animmediate release component. The IR component may be an enhancedimmediate release composition. The enhanced immediate releasecomposition may be characterized by a faster in vitro topiramate releaseas compared to the IR formulation. Preferably, at least 80% of an activecompound from the enhanced immediate release composition is released ina time period of not more than 30 minutes. More preferably, at least 50%of an active compound from the enhanced immediate release composition isreleased in a time period of not more than 10 minutes, and at least 25%is dissolved in a time period of not more than 5 minutes after the oraladministration. In the most preferred embodiment of the presentinvention, at least 75% of the active compound is released from the EIRcomposition in a time period of not more than 10 minutes. The embodimentin which the IR component is an enhanced immediate release compositionwill be discussed in more details below.

In addition to topiramate and inactive excipients, the EIR compositionof the present invention comprises at least one agent selected from agroup consisting of complexing agents and enhancing agents.

Without any limitation, the enhancing agents suitable for the presentinvention may be selected from the solubility enhancing agents,dissolution enhancing agents, absorption enhancing agents, penetrationenhancing agents, surface active agents, such as non-ionic surfactants,ionic surfactants or combinations thereof; stabilizers that includeantioxidants, preservatives, buffering agents, bases and other known inthe art; enzyme inhibitors, p-glycoprotein inhibitors, multidrugresistance protein inhibitors, or any combinations thereof. Therepresentative, but non-limiting examples of these compounds are VitaminE TPGS, amino acid such as glutamic acid and glycine, sorbitol, mannose,amylose, maltose, mannitol, lactose, sucrose, glucose, xylitose,dextrins such as maltodextrin, Cremophor RH40 (glycerol-polyethyleneglycol oxystearate), Gelucire 50/13 (PEG-32 glyceryl palmitostearate),sodium lauryl sulfate, Tween 80 (polyoxyethylene sorbitan monooleate),benzyl alcohol, Span 20 (sorbitan monolaurate), Poloxamer 407, PEG3350,PVP K25, oleic acid, Capmul GMO (glyceryl monooleate), sodium benzoate,cetyl alcohol, sucrose stearate, crospovidone, sodium starch glycolate,crosscarmellose sodium, carboxymethylcellulose, starch, pregelatinizedstarch, HPMC, substituted hydroxypropylcellulose, microcrystallinecellulose, sodium bicarbonate, calcium citrate, sodium docusate, andmenthol, among others. Enhancers can be combined to achieve multipleenhancement effects, for example, solubility enhancement combined withpermeability enhancement and p-glycoprotein inhibition, or to provide asynergistic enhancement effect to achieve greater and more efficientenhancement. For example, polyglycolized glycerides (different grades ofGelucire) can be combined with sodium lauryl sulfate to achieve highersolubility enhancement as well as faster dissolution of topiramate.

In one embodiment, the EIR composition comprises a highly solublecomplex of topiramate with a complexing agent that is represented by,but not limited to, cyclodextrins, including cyclodextrin derivatives,such as hydroxypropyl-beta-cyclodextrin, beta-cyclodextrin,gamma-cyclodextrin, and alpha-cyclodextrin. The ratio of cyclodextrin totopiramate in the EIR formulation is preferably less than 20:1 and morepreferably less than 5:1. In the most preferred embodiment, thecomplexing agent is hydroxypropyl beta cyclodextrin.

The highly soluble complex of topiramate and cyclodextrin is prepared bymixing topiramate and cyclodextrin together in the presence of water.The concentration of cyclodextrin is preferably high to facilitate theformation of topiramate-enhancer complex. In the case when thecomplexing agent is hydroxypropyl-beta-cyclodextrin, the concentrationof the hydroxypropyl-beta-cyclodextrin solution used for mixing withtopiramate is greater than 2%, preferably greater than 20%, and morepreferably at least about 40%. The amount of topiramate is determined bya desired ratio of hydroxypropyl-beta-cyclodextrin to topiramate, whichis preferably less than 20:1, and more preferably less than 5:1. Themixing time of the complex solution is from about one hour to about 48hours, and preferably from about 5 hours to about 24 hours. The additionof hydroxypropyl-beta-cyclodextrin and topiramate can be incremental toreduce the viscosity of the complex solution and to achieve bettercomplexation.

In a further embodiment, the EIR component of the present invention iscontained in at least one bead population. Topiramate EIR beads can beprepared using processes suitable for bead manufacturing, such ascoating of a topiramate suspension, dispersion or solution onto an inertcarrier, or by roller compaction, granulation, extrusion/spheronization,or powder coating, and are not limited by the examples cited therein.The enhancing agents of the present invention can be incorporated intothe topiramate containing beads, or may be contained in other beadsseparated from the topiramate containing beads. By way of a non-limitingexample, topiramate-containing EIR beads were prepared by coatingtopiramate dispersion onto an inert carrier such as sugar spheres. Thetopiramate dispersion, in addition to topiramate in the micronized formor in non-micronized form, can contain one or more enhancers, water andoptionally a binder such as hydroxypropylcellullose,hydroxypropylmethylcellulose, polyvinylpyrrolidone and polyvinylalcohol.

When the formulation is enhanced with complexing agents, the agents maybe first mixed with topiramate and a suitable solvent such as water toform the complex. The topiramate-containing complex is then mixed with abinder solution prepared separately to give the coating dispersion. Thecoating dispersion is then sprayed onto the inert carrier such as sugarspheres using a fluid bed processor.

In an alternative embodiment of the invention, the formulation comprisesat least one XR bead population, and at least one additional combinationbead population consisting of the extended release beads that have anadditional immediate release component layer coated on top of therelease controlling coating. This layer may be formed by a suitableloading method such as solution/suspension/dispersion coating, powdercoating or wet granulation.

In yet another embodiment, at least part (i.e., more than 0.01%,preferably at least 1%) of the active ingredient may be present in theformulation in a form of micronized particles with the size of from 1 μmto 1000 μm, preferably from 2 μm to about 200 μm, more preferably from 2μm to about 100 μm. Further, one or more enhancers may be present in theformulations covered by this embodiment. The enhancers are selected fromsolubility enhancing agents, dissolution enhancing agents, absorptionenhancing agents, penetration enhancing agents, surface active agents,such as non-ionic surfactants, ionic surfactants or combinationsthereof; stabilizers that include antioxidants, preservatives, bufferingagents, bases and other known in the art; enzyme inhibitors,p-glycoprotein inhibitors, multidrug resistance protein inhibitors, orany combinations thereof. Preferably, the enhancer is a solubilityenhancer or a dissolution enhancer.

The topiramate formulation of the present invention may be formulated ina dosage form selected from a tablet, a pill, a capsule, a caplet, atroche, a sachet, a cachet, a pouch, sprinkles, or any other formsuitable for oral administration.

In one embodiment of the invention, the dosage form is a gelatin capsulecontaining the XR component in a form of at least one population ofbeads, and an optional IR component. The IR component, when present, maybe in a form of a powder, or may also be contained in at least onepopulation of beads to achieve faster dissolution of topiramate (FIG.5).

In an alternative embodiment, part of the total amount of the activeingredient may be incorporated into the afore-mentioned bead populationsthat will be contained inside an enclosure such as a capsule, and therest of the active ingredient can be loaded on the outside of theenclosure by a suitable loading method such assolution/suspension/dispersion coating or powder coating or wetgranulation. For example, a part of the immediate release topiramateformulation can be loaded by coating on the outside of a capsule thatcontains within it other populations of topiramate such as extendedrelease topiramate. This dosage form can provide almost instantaneousdissolution of the initial portion of topiramate dose from the outsideof the capsule, followed by a sustained release of the rest oftopiramate from inside the capsule.

In a further embodiment of the invention, the dosage form is a tablet.Without imposing any limitations, this embodiment may be exemplified bya multilayered tablet that comprises at least one layer containing theextended release component, and at least one layer comprising theimmediate release component, wherein the IR component may or may be notan EIR composition.

The last two embodiments are especially beneficial when fast onset ofaction followed by sustained release is preferred, as is for example inthe cases of a breakthrough migraine episode.

The current invention additionally encompasses a method of preparingformulations of topiramate, comprising an extended release component,and an optional immediate release component, wherein topiramate isreleased from the formulation at the sustained rate along thepre-determined release profile. The method comprises the followingsteps:

1. determining the desired release profile;

2. determining specific amounts of the extended release component andthe immediate release component necessary to produce the pre-determinedrelease profile; and

3. incorporating the specified amounts of the components into theformulation.

In one embodiment, the method comprises a step for providing animmediate release component, which may be an enhanced immediate releasecomposition.

In another embodiment, the method includes a process for providing anextended release component contained in at least one population of beadscharacterized by its own rate of release, wherein the process includesthe steps of:

1. forming at least one population of topiramate-containing beads;

2. coating each population of beads with its own coating solution;

3. curing the coating for a period of time to produce a releasecontrolling coating specific for each bead population, and

4. incorporating the beads into the formulation.

The exact amount of beads of every population incorporated into theformulation and into the final dosage form is determined using thelinear superposition principle (WinNonLin) on the basis of thepharmacokinetic data of the separate bead populations and thepre-determined release profile (Example 6).

Release profiles of XR topiramate beads can be selectively adjusted,modified or stabilized by curing the beads at an elevated temperature.This process is well known in the art. However, it was unexpectedlydiscovered that curing the beads in the curing apparatus in the presenceof at least one suitable solvent dramatically reduces the curing timenecessary to produce a desired release profile and a level of stability.The curing process that previously required up to two weeks can becarried out by the method of current invention in several hours.

The assisting solvents can be selected from those solvents that candissolve or partially dissolve the coating material, or those that caninduce or assist the coalescence or molecular relaxation of the coatingmaterial, or those that can reduce electrostatic charge on the dosageforms during curing and those that can facilitate curing at a highertemperature. Examples of these solvents include but are not limited toorganic solvents, such as alcohols, ketones, ethers, esters, amides,amines, hydrocarbons including substituted hydrocarbons such aschlorinated hydrocarbons and aromatic hydrocarbons, furans, sulfoxides,organic acids, phenols, super-critical fluids; ammonia; and water,buffered water, or water solutions of other inorganic or organiccompounds, and their combinations. Preferably, water, water-alcoholmixture, water-ketone mixture, water-ammonia mixture, or water-organicacid (for example water-acetic acid) mixture, or combinations thereofare used as the assisting solvents.

The curing of the dosage form normally is done in an apparatus that canoperate at elevated temperatures and that can deliver the assistingsolvents by means such as spray, injection, or vaporization. In theembodiment of the invention when the assisting solvent is sprayed orinjected into the curing apparatus, the stream of solvent is introduceddirectly onto the coated beads. The amount of the solvent necessary toproduce the desired effect, such as the desired release parameters andstabilization of the coating, depends on the nature of the solvent andthe method of solvent delivery.

Typically, when the vaporization method is used, the organic solventsand aqueous solutions may be used in the wide range of vaporconcentrations varying from 2% to more than 100%, providing anunsaturated, saturated or an oversaturated atmosphere. The pure water,however, has to be used in such an amount as to provide at least asaturated or, preferably, an oversaturated atmosphere in the curingapparatus. At least during the delivery of assisting solvents, thecoated beads are mixed or agitated either continuously or in a pulsedmanner.

In an alternative embodiment of the invention, hot water steam isintroduced into the curing apparatus for a pre-selected period of time.The steam serves simultaneously as a solvent and as a source of heat forthe beads. Introduction of steam is followed by a drying period.

This method of curing the release controlling coating results in manybenefits including the dramatically shortened curing time, increasedstability and modification of the release profile, and is not limited totopiramate containing beads, but includes the curing of anymicroparticles regardless of the drug.

Specifically, active ingredient containing beads, with or without theoptional over-coat, are charged to a fluid bed processor or a pan coaterand heated to a desired curing temperature range, for example 40° C. to80° C. for sustained release dosage forms containing ethylcellulose(SURELEASE®), and 40° C. to 70° C. for sustained release dosage formscontaining acrylic polymers (EUDRAGIT® RS and EUDRAGIT® RL ammoniomethacrylate copolymer dispersion, type A and B)). The assisting solventor solvents, such as water or alcohol-water mixture, are sprayed ontothe beads while mixing by, for example, fluidizing or rotating.Alternatively, the process is carried out in an oven where hot steam isintroduced as previously discussed. Solvent-assisted curing is carriedout to a desired curing time length, either in one curing period or inmultiple, separate curing periods. The dosage forms can be further driedfor a short period of time to remove residual solvents.

The solvent-assisted curing process significantly accelerates the curingof release controlling coating on active ingredient containing beads ascompared to the heat-only curing of the same. In most instances, lessthan 4 hours of solvent-assisted curing resulted in more complete curingof the extended release dosage forms than 2 weeks of heat-only ovencuring of the same dosage forms.

The present invention also presents a method of treatment or preventionof a pathological condition in a mammalian subject, comprising orallyadministering to the subject a therapeutically effective amount of anovel topiramate formulation of the instant invention, whereintopiramate is released from the formulation at a sustained rate alongthe pre-determined release profile. The method of the current inventionpossesses the flexibility to selectively adjust the pharmacokinetics ofthe administered formulations depending on the nature of the conditionand needs of the patients due to the novel design of the topiramateformulation that comprises an extended release component and an optionalimmediate release component, and the release profiles of both componentscan be selectively modified during the preparation process as describedabove to comply with the predetermined release profile.

The pathological condition that may be treated by a method of thepresent invention is a neurological condition, psychiatric condition,diabetes and related disorders, cardiovascular condition, obesity, andany other condition or disorder that may be treated or prevented by thetopiramate administration.

The neurological disorders that may be treated or prevented by aformulation of the present invention include, but are not limited to,epilepsy, migraine, essential tremor, restless limb syndrome, clusterheadaches, neuralgia, neuropathic pain, Tourrette's syndrome, infantilespasms, perinatal hypoxia ischemia and related damage, chronicneurodegenerative disorders, acute neurodegeneration, and ALS.

Psychiatric disorders that may be treated or prevented by a formulationof the present invention include, but are not limited to bipolardisorder, dementia, depression, psychosis, mania, anxiety,schizophrenia, obsessive-compulsive disorder, post-traumatic stressdisorder, ADHD, impulse control disorders, border line personalitydisorder, addiction, and autism.

Formulations of the present invention may be also used for the treatmentand prevention of diabetes and related disorders, such as type IIdiabetes mellitus, diabetic retinopathy, impaired oral glucosetolerance, diabetic skin lesions, diabetic neuropathy, Syndrome X andelevated blood glucose levels; ocular disorders, including but notlimited to glaucoma and macular degeneration; cardiovascular disordersrepresented but not limited to elevated blood pressure and elevatedlipids; obesity; asthma; autoimmune disorders; sleep apnea and sleepdisorders. The formulations may be also used for inducing weight loss orpromoting wound healing, or for any other condition, not specifiedabove, wherein the use of topiramate is indicated.

The invention will be further illustrated by the following Examples,however, without restricting its scope to these embodiments.

EXAMPLES Example 1 Extended Release Beads Preparation

Topiramate Drug Layering on Sugar Spheres—The “Core”

An aqueous suspension of 10-20% (w/w) topiramate (particle size 90% vol.NMT 30 micrometer, 50% vol. NMT 15 micrometer and 10% vol. NMT 5micrometer) and 0.5-4% (w/w) HPMC or other aqueous binder can be used asthe drug layering coating solution. A fluid bed suited for Wurster-sprayis assembled and charged with inert carriers such as sugar spheres. Thecoating suspension is sprayed onto the bed to evenly coat the inertcarriers to a desired topiramate loading level. Higher binderconcentration in the coating solution may be used for smaller size inertcarrier and higher topiramate loading. Inlet airflow rate and producttemperature are adjusted to keep the batch from spray-drying the coatingmaterial or over-wetting the spheres.

Coating of the Core with a Release Controlling Coating

A dispersion of a cellulosic polymer such as ethylcellulose andmethylcellulose can be used to coat the core in the current invention.Ethylcellulose dispersion (SURELEASE®) can be diluted to a finalconcentration of about 10% to about 20% and with or without the use ofother ingredients such as pore formers. A fluid bed suited forWurster-spray is assembled and charged with the cores prepared inExample 1. The release controlling coating dispersion is sprayed ontothe bed to evenly coat the core to a desired coating level asexemplified in Table 1.

TABLE 1 Composition and process Parameters for the extended ReleaseTopiramate Beads XR1a XR1b XR1c XR2a XR2b XR2c XR2d RC* coatingEthylcellulose Ethylcellulose Ethylcellulose EthylcelluloseEthylcellulose Ethylcellulose Ethylcellulose material (SURE- (SURE-(SURE- (SURE- (SURE- (SURE- (SURE- LEASE ®) LEASE ®) LEASE ®) LEASE ®)LEASE ®) LEASE ®) LEASE ®) Pore-former — — OPARDY ® — — OPARDY ®OPARDY ® Clear Clear Clear RC coating — — 80:20 — — 80:20 80:20 materialto pore-former ratio RC coating 2% 4% 3% 3% 3% 6.5% 6.5% level Product20° C.-60° C. 20° C.-60° C. 20° C.-60° C. 20° C.-60° C. 20° C.-60° C.20° C.-60° C. 20° C.-60° C. temperature during coating Over-coat —OPARDY ® OPARDY ® — OPARDY ® — OPARDY ® material AMB White AMB White AMBWhite AMB White Over-coat — 1.5% 1.5% — 1.5% — 1.5% coating level CuringFluid bed/ Fluid bed/ Fluid bed/ Fluid bed/ Fluid bed/ Fluid bed/ Fluidbed/ method water, or water, or water, or water, or water, or water, orwater, or oven oven oven oven oven oven oven XR3 XR4 XR5 XR6 XR7 XR8 RCcoating material Ethylcellulose Ethylcellulose EthylcelluloseEthylcellulose Ethylcellulose Acrylic SURE- SURE- SURE- SURE- SURE-polymers LEASE ® LEASE ® LEASE ® LEASE ® LEASE ® (EUDRAGIT ® RL30D/RS30D) Pore-former — Cellulosic Cellulosic Cellulosic Cellulosic —polymers polymers polymers polymers (OPADRY ® (OPADRY ® (OPADRY ®(OPADRY ® Clear) Clear) Clear) Clear) RC coating material to — 80:2080:20 80:20 85:15 — pore-former ratio RC coating level 3.7% 3.1% 5.2%9.5% 15% 15% Product temperature 20° C.-60° C. 20° C.-60° C. 20° C.-60°C. 20° C.-60° C. 20° C.-60° C. 20° C.-60° C. during coating Over-coatmaterial — — — — — — Over-coat coating level — — — — — — Curing methodFluid Fluid Fluid bed/ Fluid Fluid bed/ Fluid bed/ bed/water, orbed/water, or water, or oven bed/water, or water, fluid water, fluidoven oven oven bed/5% bed/5% alcohol- alcohol- water, or water, or ovenoven *RC—Release Controlling

Example 2 Method of Topiramate-Hydroxypropyl-beta-cyclodextrin ComplexBead Preparation

Approximately half of the intended amount of topiramate was added to thewater with constant mixing followed by sprinkling ofhydroxypropyl-beta-cyclodextrin into the dispersion. Once the dispersionbecame significantly less viscous, more drug substance was addedfollowed by sprinkling of more hydroxypropyl-beta-cyclodextrin. The drugand hydroxypropyl-beta-cyclodextrin addition steps were repeated, andthe dispersion was mixed for 12-18 hours. Separately,hydroxypropylmethylcellulose was dissolved in water. The abovetopiramate-hydroxypropyl-beta-cyclodextrin dispersion andhydroxypropylmethylcellulose solution were mixed together for 15 to 30minutes and the mixture was screened through an 80-mesh sieve. Theresultant dispersion was sprayed onto sugar spheres using a fluid bedprocessor to yield the enhanced immediate release beads (Table 2).

TABLE 2 Hydroxypropyl-beta-cyclodextrin - Topiramate EIR BeadCompositions Percentage (w/w) in Beads EIR-1 EIR-2 EIR-3 EIR-4 Component(HPBCD:Drug = 3:2)* (HPBCD:Drug = 3:2)* (HPBCD:Drug = 1:1)* (HPBCD:Drug= 1:2)* Topiramate 25.0 3.3 28.9 33.3 Hydroxypropyl-beta- 37.5 4.95 28.916.7 cyclodextrin Hydroxypropylmethylcellulose 3.1 0.41 2.4 4.2 Sugarspheres 34.4 91.34 39.8 45.8 *HPBCD:Drug -Hydroxypropyl-beta-cyclodextrin to drug substance ratio

Example 3 Topiramate EIR Beads Containing Non-Complexing Enhancers

Topiramate is dispersed in a binder solution, such ashydroxypropylmethylcellulose solution, that contains an appropriateamount of enhancer or enhancers such as d-alpha-tocopheryl polyethyleneglycol 1000 succinate (vitamin E TPGS) and sodium lauryl sulfatecombination, polyoxyl hydrogenated castor oil (different grades ofCremophor RH), polyglycolized glycerides (different grades of Gelucire),polyglycolized glycerides (different grades of Gelucire) combined withsodium lauryl sulfate, or combinations thereof. The resultant dispersionis sprayed onto an inert carrier such as sugar spheres using a fluid bedprocessor to achieve a desired drug load (Table 3).

TABLE 3 Enhanced Immediate Release Topiramate Bead CompositionsPercentage (w/w) in Beads Component EIR-5 EIR-6 EIR-7 Topiramate 36.8 37.9  36.4  Sodium lauryl sulfate 0.7 0.5 — D-alpha-tocopheryl 7.3 — —polyethylene glycol 1000 succinate Polyoxyl hydrogenated castor — — 9.1oil (Cremophor RH40) Polyglycolized glycerides — 4.7 — (Gelucire 50/13)Hydroxypropylmethylcellulose 4.6 4.8 4.5 Sugar spheres 50.6  52.1  50.0 

Example 4 Topiramate EIR Beads Containing Micronized Particles

Miconized or non-micronized topiramate is dispersed in a solution withor without heating, optionally containing dissolution enhancing agentssuch as mannose, maltose, mannitol, lactose, maltodextrin and sodiumstarch glucolate, and optionally containing one or more additionalenhancers such as PEG3350, sodium lauryl sulfate, sodium docusate,polyoxyethylene sorbitan monooleate and Poloxamers, under such processparameters that topiramate particles that remain undissolved have aparticle size of about 2 micron to about 30 micron. A particle sizereduction device such as a homogenizer can also be used to reduce theparticle size of undissolved topiramate. The resultant topiramatedispersion is then sprayed onto inert carriers such as sugar spheres ina coating processor such as a fluid bed processor. The formulationsobtained are represented in the Table 4:

TABLE 4 Topiramate EIR Beads containing micronized particles Percentage(w/w) in Beads EIR- EIR- EIR- EIR-8 EIR-9 EIR-10 11 12 13 Topiramate 3.226.0 25.0 3.2 26.0 26.0 Mannose 0.4 5.0 3.3 2.0 10.0 10.0 Maltrin 250 —— 1.0 1.0 — — PEG3350 1.0 15.0 — — — 10.0 Sodium lauryl — — — — 0.5 —sulfate Hydroxypropyl-beta- — — 37.5 — — — cyclodextrinD-alpha-tocopheryl — — — — 2.0 — polyethylene glycol 1000 succinatePolyoxyl — — — — — 2.0 hydrogenated castor oil (Cremophor RH40) Sugarspheres 95.4 54.0 33.2 93.8 61.5 52.0

Example 5

Method of Curing Beads

The topiramate beads coated with a release controlling coating, with orwithout an overcoat, can be cured using the above-mentionedsolvent-assisted curing process, or using the heat-only curing process,to a desired curing level and preferably to complete curing.

Specifically, the core is coated to a desired coating level with asolution or dispersion of the release controlling coating material, withor without the above-mentioned additives such as pore-formers, using afluid bed processor or any other suitable apparatus for coating of thecore. Product temperature is controlled at a desirable range, forexample 20° C. to 60° C. for the coating of ethylcellulose (SURELEASE®)and 20° C. to 60° C. for acrylic polymers (EUDRAGIT® RL and Eudragit®EUDRAGIT® RS grades).

An optional overcoat with materials such as cellulosic polymers (variousOPADRY®) is applied thereafter. Curing of the sustained releasetopiramate beads is carried out either in an oven at 40° C. to 80° C.for SURELEASE® containing beads or at 40° C. to 70° C. for EUDRAGIT® RLor RS containing beads, or in a fluid bed processor with or without theuse of assisting solvents at similar product temperatures.

For curing that uses assisting solvents, the assisting solvent can bedelivered through top spray, bottom spray, side spray or injection, orintroduced by vaporization. Preferably, water, water-alcohol mixture,water-ketone mixture, water-ammonia mixture, or water-organic acid (forexample water-acetic acid) mixture, or combinations thereof are used asthe assisting solvents.

Example 6 Sustained Release Formulations of Topiramate

a. Plasma concentration versus time curves for the topiramateformulations containing extended release and immediate release beadpopulations are simulated using WinNonlin Version 5.0.1 based on thepharmacokinetic data on the separate bead populations that weregenerated in a comparative randomized single-dose 6-way crossover studyin healthy adult volunteers. The study included administration of a 50mg oral dose of three extended release compositions, designated here asXR1, XR2 and XR3, two immediate release compositions ((TOPAMAX®,Ortho-McNeil Neurologics, Inc.) (25 mg BID), and an immediate releasebead formulation) and an enhanced immediate release (IR) beadcomposition. The single dose topiramate plasma concentration profilesfor XR1, XR2 and XR3 are shown in FIG. 3. The single dose topiramateplasma concentration profiles for IR are shown in FIG. 4. The data areprojected to a steady-state (SS) with a 24 h dosing interval for thesustained release compositions and a 12 h dosing interval for TOPAMAX®,using the linear superposition principle (WinNonlin). The extendedrelease populations XR1, XR2 and XR3, and an immediate release (IR)population are selected in such a way as to be defined by at least oneof the three following sets of conditions:

1. for the steady state,

for XR1, 1.70 C_(maxIR)>=C_(maxXR1)>=1.30 C_(maxIR)

for XR2, 0.40 C_(maxIR)>=C_(maxXR2)>=0.20 C_(maxIR)

for XR3, 0.25 C_(maxIR)>=C_(maxXR3)>=0.05 C_(maxIR)

2. for in-vitro dissolution,

for XR1, 1.5 h<=T_(80%)<=4 h

for XR2, 5 h<=T_(80%)<=8 h

for XR3, 8 h<T_(80%)<=10 h

3. for a single initial dose in-vivo,

for XR1, 4 h<=T_(max)<=8.5 h

for XR2, T_(max)>=16 h

for XR3, T_(max)>=16 h.

Optionally, the immediate release bead population is composed ofenhanced immediate release (EIR) beads such that at least one conditionis true: a. for the steady state, 2.40 CmaxIR>=CmaxEIR>=1.20 CmaxIR; b.for in-vitro dissolution, T80%<=30 min; c. for a single initial dosein-vivo, Tmax<=2 h.

The results of the pharmacokinetic simulation for the seven exemplaryformulations are summarized in Table 5 below. These formulations areselected as examples only, and in no way limit the range, compositionsor properties of the formulations covered by the present invention.

TABLE 5 Composition and Pharmacokinetic data of Multi-bead Formulations#1 #2 #3 #4 #5 #6 #7 % XR1 20 50 0 10 10 15 0 % XR2 80 0 85 85 80 70 100% XR3 0 50 0 0 15 0 % IR 0 0 15 5 10 0 0 Rel. BA (%), 98.5 100.5 96.697.4 97.6 97.3 96.0 SS Degree of 0.15 0.22 0.14 0.14 0.15 0.13 0.09fluctuation, SS

b. based on the results of WinNonlin simulation discussed in part (a),formulations #1 (A), #3 (B), and #4 (C) were tested in the comparativerandomized multi-dose 4-way study following a once a day 50 mg oral doseof three controlled release formulations and a 25 mg twice a day oraldoses of TOPAMAX® in healthy adult volunteers.

The results of the study are summarized in Table 6 and FIG. 6:

TABLE 6 Pharmacokinetic study data for Multi-bead Formulations Control#1 A #3 B #4 C (TOPAMAX ®) % XR1 20 0 10 — % XR2 80 86 84 — % XR3 0 0 0— % IR 0 14 6 — Rel. BA (%), 92 93 95 100 SS Relative 73% 72% 66% 100%Degree of fluctuation, SS

1. A sustained release formulation of topiramate for oral administrationto a mammalian subject comprising an immediate release bead population(IR), a first extended release bead population (XR1), and a secondextended release bead population (XR2), wherein: (a) the IR beadpopulation comprises topiramate up to 10% by wt of the total amount oftopiramate in the formulation and 0.1-10% by wt of a binder, wherein thetopiramate and binder form a coating on inert carrier particles, whereinthe coated inert carrier particles are not coated with a releasecontrolling coating, and wherein the IR bead population releases greaterthan or equal to 80% of its topiramate in a continuous manner over lessthan or equal to 1 hour; (b) the XR1 bead population comprisestopiramate up to 20% by wt of the total amount of topiramate in theformulation, wherein the topiramate is a coating on inert carrierparticles, wherein the topiramate coated inert carrier particles arefurther coated with a release controlling coating material, wherein thecoating material comprises 2-15% by weight of the topiramate coatedinert carrier particles, and wherein the XR1 bead population releases80% of its topiramate in a continuous manner over less than or equal to4 hours; and, (c) the XR2 bead population comprises topiramate at least80% by weight of the total amount of topiramate in the formulation,wherein the topiramate is a coating on inert carrier particles, whereinthe topiramate coated inert carrier particles are coated with a releasecontrolling coating material, wherein the coating material comprises2-15% by weight of the topiramate coated inert carrier particles, andwherein the XR2 bead population releases 80% of its topiramate in acontinuous manner over less than 8 hours; wherein the releasecontrolling coating materials comprise methylcellulose, ethylcellulose,hydroxypropyl cellulose, hydroxypropylmethyl cellulose, celluloseacetate, cellulose acetate phthalate, polyvinyl alcohol, polyacrylates,polymethacrylates or copolymers thereof, and wherein the XR1 and XR2bead populations have their own specific rates of release.
 2. Thesustained release foimulation according to claim 1, wherein the binderis selected from the group consisting of starches, microcrystallinecellulose, hydroxypropyl cellulose, hydroxyethyl cellulose,hydroxypropylmethyl cellulose, and polyvinylpyrrolidone.
 3. Thesustained release formulation according to claim 1, wherein the IR beadpopulation further comprises an enhancing agent selected from the groupconsisting of Vitamin E TPGS, glutamic acid, glycine, sorbitol, mannose,amylose, maltose, mannitol, lactose, sucrose, glucose, xylitose,dextrins, glycerol-polyethylene glycol oxystearate, polyethyleneglycol-32 glyceryl palmitostearate, sodium lauryl sulfate,polyoxyethylene sorbitan monooleate, benzyl alcohol, sorbitanmonolaurate, polyethylene-polypropylene glycol, polyethyleneglycol-3350, polyvinylpyrrolidone-K25, oleic acid, glyceryl monooleate,sodium benzoate, cetyl alcohol, sucrose stearate, crospovidone, sodiumstarch glycolate, croscarmellose sodium, carboxymethylcellulose, starch,pregelatinized starch, hydroxypropylmethylcellulose HPMC, substitutedhydroxypropylcellulose, microcrystalline cellulose sodium bicarbonate,calcium citrate, sodium docusate, menthol, and combinations thereof. 4.The sustained release formulation according to claim 1, wherein the IRbead population further comprises a complexing agent selected from thegroup consisting of cyclodextrin, hydroxypropyl-beta-cyclodextrin,beta-cyclodextrin, gamma-cyclodextrin, alpha-cyclodextrin, andderivatives thereof.
 5. The sustained release formulation according toclaim 1, wherein the XR1 and/or XR2 bead populations further comprises apore former selected from the group consisting of glucose, fructose,mannitol, mannose, galactose, sorbitol, pullulan, dextran,hydroxyalkylcelluloses, carboxyalkylcelluloses,hydroxypropylmethylcellulose, cellulose ethers, acrylic resins,polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, polyethyleneoxide, carbomer, diols, polyols, polyhydric alcohols, polyalkyleneglycols, polyethylene glycols, polypropylene glycols or block polymersthereof, polyglycols, poly(α-ω)alkylenediols; alkali metal salts andalkaline earth metal salts, and combinations thereof.
 6. The formulationof claim 1, wherein the IR bead population releases greater than orequal to 80% of its topiramate in less than or equal to 30 minutes. 7.The formulation of claim 1, wherein at least a part of the activeingredient is in a form of micronized particles.
 8. The formulation ofclaim 1, wherein said formulation is in a dosage form of a tablet, apill, a capsule, a caplet, a troche, a pouch, or sprinkles.
 9. Theformulation of claim 1, wherein the total amount of topiramate in theformulation is from 0.5 to 3000 mg.
 10. The formulation of claim 1,wherein the inert carrier particles comprise cellulose spheres, silicondioxide, starch or sugar spheres.
 11. The sustained release formulationaccording to claim 1, wherein the coating material comprisesmethylcellulose, ethylcellulose, hydroxypropyl cellulose, orhydroxypropylmethyl cellulose.
 12. The formulation of claim 1, whereinsaid formulation provides for a maximum steady state plasmaconcentration (Cmax) of topiramate which is in the range from 50% to125% of the maximum plasma concentration produced by the same amount oftopiramate administered as an immediate release formulation BID.
 13. Theformulation of claim 1, wherein said formulation provides for a relativesteady state AUC in the range of 80% to 125% of the AUC of the sameamount of topiramate administered as an immediate release formulationBID.
 14. The formulation of claim 1, further comprising an additionalpharmaceutically active ingredient in combination with topiramate.
 15. Amethod of treatment of a neurological and/or psychiatric condition in amammalian subject, comprising orally administering to the subject atherapeutically effective amount of the sustained release formulation ofclaim
 1. 16. The method of claim 15, wherein said condition is selectedfrom a group consisting of epilepsy, migraine, essential tremor,restless limb syndrome, cluster headaches, neuralgia, neuropathic pain,Tourrette's syndrome, infantile spasms, bipolar disorder, dementia,depression, psychosis, mania, anxiety, schizophrenia,obsessive-compulsive disorder, post-traumatic stress disorder, attentiondeficit hyperactivity disorder, impulse control disorders, border linepersonality disorder, addiction, autism, chronic neurodegenerativedisorders, acute neurodegeneration, amyotrophic lateral sclerosis. 17.The method of claim 15, wherein the condition is epilepsy.
 18. Themethod of claim 15, wherein the condition is migraine.
 19. A sustainedrelease formulation of topiramate comprising: (a) a first extendedrelease bead population (XR1) comprising up to 20% by wt of the totalamount of topiramate in the formulation, wherein the topiramate is acoating on inert carrier particles and further coated with a releasecontrolling coating material, wherein the release controlling materialreleases 80% of the topiramate in a continuous manner over less than orequal to 4 hours; and, (b) a second extended release bead population(XR2) comprising at least 80% by weight of the total amount oftopiramate in the formulation, wherein the topiramate is coated ontoinert carrier particles and further coated with a release controllingcoating material, wherein the release controlling material releases 80%of the topiramate in a continuous manner over less than 8 hours; whereinthe release controlling coating materials comprise methylcellulose,ethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,cellulose acetate, cellulose acetate phthalate, polyvinyl alcohol,polyacrylates, polymethacrylates or copolymers thereof; and wherein theXR1 and XR2 bead populations have their own specific rates of release.20. The sustained release formulation according to claim 19, furthercomprising: (c) an immediate release (IR) bead population comprisestopiramate up to 10% by wt of the total amount of topiramate in theformulation and 0.1-10% by wt of a binder, wherein the topiramate andbinder form a coating on inert carrier particles, and wherein the IRbead population releases greater than or equal to 80% of its topiramatein a continuous manner over less than or equal to 1 hour.
 21. Thesustained release formulation according to claim 20, wherein the IR beadpopulation further comprises an enhancing agent selected from the groupconsisting of Vitamin E TPGS, glutamic acid, glycine, sorbitol, mannose,amylose, maltose, mannitol, lactose, sucrose, glucose, xylitose,dextrins, glycerol-polyethylene glycol oxystearate, polyethyleneglycol-32 glyceryl palmitostearate, sodium lauryl sulfate,polyoxyethylene sorbitan monooleate, benzyl alcohol, sorbitanmonolaurate, polyethylene-polypropylene glycol, polyethyleneglycol-3350, polyvinylpyrrolidone-K25, oleic acid, glyceryl monooleate,sodium benzoate, cetyl alcohol, sucrose stearate, crospovidone, sodiumstarch glycolate, croscarmellose sodium, carboxymethylcellulose, starch,pregelatinized starch, hydroxypropylmethylcellulose, substitutedhydroxypropylcellulose, microcrystalline cellulose sodium bicarbonate,calcium citrate, sodium docusate, menthol, and combinations thereof. 22.The sustained release formulation according to claim 19, furthercomprising: (c) a third extended release bead population (XR3)comprising up to 15% by weight of the total amount of topiramate in theformulation, wherein the topiramate is coated onto inert carrierparticles and further coated with a release controlling coatingmaterial, wherein the release controlling material releases 80% of thetopiramate in a continuous manner over less than or equal to 10 hours.23. The sustained release formulation according to claim 19, wherein theXR1 and/or XR2 bead populations further comprises a pore former selectedfrom the group consisting of glucose, fructose, mannitol, mannose,galactose, sorbitol, pullulan, dextran, hydroxyalkylcelluloses,carboxyalkylcelluloses, hydroxypropylmethylcellulose, cellulose ethers,acrylic resins, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone,polyethylene oxide, carbomer, diols, polyols, polyhydric alcohols,polyalkylene glycols, polyethylene glycols, polypropylene glycols orblock polymers thereof, polyglycols, poly(α-ω)alkylenediols; alkalimetal salts and alkaline earth metal salts, and combinations thereof.24. The sustained release formulation according to claim 19, wherein thecoating material comprises methylcellulose, ethylcellulose,hydroxypropyl cellulose, or hydroxypropylmethyl cellulose.
 25. Theformulation of claim 19, wherein said formulation provides for arelative steady state AUC in the range of 80% to 125% of the AUC of thesame amount of topiramate administered as an immediate releaseformulation BID.
 26. The formulation of claim 19, further comprising anadditional pharmaceutically active ingredient in combination withtopiramate.
 27. A method of treatment of a neurological and/orpsychiatric condition in a mammalian subject, comprising orallyadministering to the subject a therapeutically effective amount of thesustained release formulation of claim
 19. 28. The method of claim 27,wherein said condition is selected from a group consisting of epilepsy,migraine, essential tremor, restless limb syndrome, cluster headaches,neuralgia, neuropathic pain, Tourrette's syndrome, infantile spasms,bipolar disorder, dementia, depression, psychosis, mania, anxiety,schizophrenia, obsessive-compulsive disorder, post-traumatic stressdisorder, attention deficit hyperactivity disorder, impulse controldisorders, border line personality disorder, addiction, autism, chronicneurodegenerative disorders, acute neurodegeneration, amyotrophiclateral sclerosis.
 29. The method of claim 28, wherein the condition isepilepsy.
 30. The method of claim 28, wherein the condition is migraine.